Agent remains controversial despite positive results

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Patients with relapsing multiple sclerosis who were free from disease activity saw continued benefits in clinical and imaging outcomes with long-term use of cladribine tablets.

Note that neither the FDA nor the European Medicines Agency has approved cladribine for MS.

NEW ORLEANS -- Patients with relapsing multiple sclerosis (MS) who were free from disease activity saw continued benefits in clinical and imaging outcomes with long-term use of cladribine tablets, researchers reported here.

"Overall rates of new clinical and MRI-detected disease activity-free status were consistently high in the group treated with cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY extension," said Kottil Rammohan, MD, of the University of Miami, and colleagues, in a presentation at the Consortium of Multiple Sclerosis Centers (CMSC).

But the use of cladribine tablets, a chemotherapy agent, in MS is not without controversy: The drug was rejected for an MS indication by European Union regulators in 2010, and the FDA denied approval of cladribine for MS in March 2011. As a result, Merck KGaA halted its development program in June 2011, but in July 2016, submitted a marketing authorization package with the European Medicines Agency.

Indeed, CMSC session moderator Aliza Ben-Zacharia, DNP, of Mt. Sinai School of Medicine in New York City told MedPage Today, "I was surprised to see cladribine on this program."

"I want to see a lot more safety work on this drug before I would want to see it used," she cautioned.

In their post-hoc analysis of the CLARITY studies, the authors found that in five treatment groups:

85.1% of 244 patients were free of new lesions after treatment with placebo and then continued treatment with 3.5 mg/kg tablets of cladribine

88.9% of 186 patients were free of new lesions after treatment with only 3.5 mg/kg tablets of cladribine for the duration of the trials

89.9% of 186 patients were free of lesions after starting treatment with 5.25 mg/kg dose of cladribine and then switching to a lower dose of the agent

80.2% of 92% patients were lesion-free after starting treatment 5.25 mg/kg dose of cladribine and then switching to placebo (P=0.036)

Also, 73% of 98 patients were free of new lesions after starting treatment with 3.5 mg/kg dose of cladribine and then switching to placebo (P=0.001 vs patients always on cladribine; (P=0.012 vs those switched to cladribine).

Rammohan also reported that the rate of infections among placebo patients in the CLARITY studies was 31.44 per 100 patient years compared with a rate of 27.12 infections per 100 patient years for individuals assigned to cladribine.

In addition, severe infections occurred at a rate of 1.08 per 100 patient years among placebo patients and a rate of 1.25 per 100 patient years among those patients who had been assigned to cladribine in the CLARITY and CLARITY extension studies.

Rammohan said 89% of patients who remained on cladribine tablets through the extension program achieved freedom from new T1 gadolinium-enhancing lesions on MRI versus 73% of the patients who had been on placebo before switching to cladribine.

He also presented data on patients who were in the gap between the end of CLARITY and the start of the CLARITY extension, some of whom were out of the program for 4 years or longer.

If the gap was ≤4 weeks, 87.5% of the patients remained free of new lesions through the end of the extension trial. If the gap was >4 weeks but <43 weeks, about 77.3% remained free of new gadolinium-enhancing lesions. If the patient was off treatment with cladribine for >43 weeks, 64.9% remained free of new lesions.

In response to a comment from a CMSC attendee, Rammohan acknowledged that patients had depleted cells for much longer than a year, and it took longer to reach a level that existed before treatment. Nonetheless, his group concluded that ""substantial proportions of patients remained free from disease activity measures in CLARITY [extension], including all subgroups, confirming the durable effect of two short annual courses of cladribine tablets, which extended for ≥2 additional years.""

Ben-Zacharia said she was not convinced. "Despite the presentation...I remain uncertain about this agent...people on cladribine have their immune cells depleted for a long period of time," she noted. "I have colleagues who were involved in the clinical trials, and they had patients who had depleted immune system cells for much longer than a year."

The study was supported by EMD Serono and Merck Serono SA, units of Merck KGaA.

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